Reservoir Explorers Find Extra HIV/SIV Pond

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Scientists at Yerkes National Primate Research Center, Emory University, have identified an additional part of the HIV reservoir, immune cells that survive and harbor the virus despite long-term treatment with antiviral drugs. The findings are published online in Immunity.

The cells display a molecule called CTLA4, the target of an FDA-approved cancer immunotherapy drug, ipilimumab. This information should help those trying to eradicate HIV from the body.

Researchers led by Mirko Paiardini, PhD, infected macaques with HIV's relative SIV and treated them with standard antiviral drugs similar to what humans receive for HIV. At the time of analysis, almost all the animals (8 out of 9) showed undetectable SIV in their blood. The team probed for CD4+ memory T cells, which are known to shelter persistent virus.

"We found that a certain group of memory CD4+ T cells displaying CTLA4, but not another co-inhibitor receptor called PD1, harbor viral DNA at higher frequencies than other groups of memory CD4+ T cells," Paiardini says. "These cells can be found in multiple tissues, such as lymph node, spleen, gut and bone marrow, and contain replication-competent and infectious virus."

Paiardini is associate professor of pathology and laboratory medicine at Emory University School of Medicine and Yerkes National Primate Research Center, and part of Emory Vaccine Center. Guido Silvestri, MD, division chief of microbiology and immunology at Yerkes and a Georgia Research Eminent Scholar, is a co-author.

The Yerkes team worked with researchers at NCI/Leidos Frederick led by Jacob Estes, PhD, using a technique called "DNAscope," to visualize latently infected cells in lymph nodes. Previous research had shown HIV-infected cells persist in regions of the lymph nodes called B cell follicles. The newly identified group of infected cells is found outside the B cell follicles.

Working in close collaboration with Rafick Sekaly, PhD, at Case Western Reserve University, the research team also showed the CTLA4-positive PD1-negative cells have the characteristics of regulatory T cells, whose job is to put a brake on the immune system and prevent it from getting too excited.

"It provides a strong rationale for targeting these cells," Paiardini says. "Depleting latently infected T-regs can not only reduce the reservoir, but also induce a stronger antiviral immune response."

The researchers also worked with Vincent Marconi, MD, a physician treating HIV in Atlanta, to confirm similar cells were present in human lymph nodes. The human samples came from six HIV-positive individuals who had been on antiviral drugs for an average of three years.

Based on the team's findings, CTLA-4 should be considered as an additional target when designing immunotherapies aimed at purging the viral reservoir, Paiardini says.

The research was supported by the National Institute of Allergy and Infectious Diseases (AI104278, AI116379, AI116171, AI110334, P30AI50409), amfAR/the Foundation for AIDS Research (109354-59-RGRL), the NIH Director's Office of Research Infrastructure Programs (Primate centers: P51OD011132) and the National Cancer Institute (Contract HHSN261200800001E).

Established in 1930, the Yerkes National Primate Research Center is a leader among the seven National Institutes of Health-funded National Primate Research Centers (NPRCs), a resource to researchers worldwide, a source of inspiration for scientific leaders of tomorrow and a provider of and advocate for quality animal care. For more than eight decades, the Yerkes Research Center has been dedicated to discovering causes, preventions, treatments and cures that will help people across generations and the world live longer, healthier lives. Today, the Yerkes Research Center is making breakthrough discoveries with our research, which is grounded in scientific integrity, expert knowledge, respect for colleagues, an open exchange of ideas and compassionate, quality animal care.

In the fields of microbiology and immunology, infectious diseases, pharmacology and drug discovery, transplantation, neurologic and psychiatric diseases, as well as behavioral, cognitive and developmental neuroscience, the basic science researchers conduct at Yerkes advances vaccine development for infectious and non-infectious diseases, paves the way for earlier diagnosis of and new treatments for life-changing illnesses, such as Alzheimer’s and Parkinson's diseases, defines the basic neurobiology and genetics of social behavior to support developing new therapies for autism spectrum and other disorders as well as drug addiction, and teaches us how interactions between genetics and the environment shape who we are.

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The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include the Emory University School of Medicine, Nell Hodgson Woodruff School of Nursing, and Rollins School of Public Health; Yerkes National Primate Research Center; Winship Cancer Institute of Emory University; and Emory Healthcare, the largest, most comprehensive health system in Georgia. Emory Healthcare includes: The Emory Clinic, Emory-Children's Center, Emory University Hospital, Emory University Hospital Midtown, Wesley Woods Center, and Emory University Orthopaedics & Spine Hospital. The Woodruff Health Sciences Center has a $2.5 billion budget, 17,600 employees, 2,500 full-time and 1,500 affiliated faculty, 4,700 students and trainees, and a $5.7 billion economic impact on metro Atlanta.